Nitrogen Heterocycles Research Articles

Palladium catalyzed ortho-C(sp2)-H activation/cyclization of aryl amines assisted by imine and vinylacetic acid.

Palladium-catalyzed directed C - H functionalization/cyclization is an effective approach for synthesizing nitrogen heterocycles. Imine, known for its ease of installation/removal, has been extensively used in the C-H activation of aldehydes, ketones, and alkylamines. Nevertheless, it has been rarely explored in the C(sp2)-H activation of aryl amines because of the generation of a strained four-membered palladacycle. Herein, an imine directed palladium catalyzed C(sp2)-H functionalization of aryl amines assisted by vinylacetic acid is established, providing access to a variety of γ-lactone fused tetrahydroquinolines under mild reaction conditions. The methodology demonstrates broad substrate scope and good functional group tolerance, representing notable advancement in organic synthesis. Mechanistic experiments are performed to clarify how the C(sp2)-H activation occurs, indicating the crucial role of vinylacetic acid. DFT calculations supports the observations, elucidating the strained four-membered ring C-H activation barrier is overcome via coordination and hydrogen bond interaction of vinylacetic acid.

Medicinal Chemistry Insights in Neuronal Nitric Oxide Synthase Inhibitors Containing Nitrogen Heterocyclic Compounds: A Mini Review.

Many scientific reports over the last two decades have focused on the discovery and development of novel nNOS inhibitors. The structural identity of isoforms, bioavailability, pharmacokinetic, and safety profile issues remain major obstacles in the discovery of more potent and selective nNOS inhibitors. This review aims to provide an in-depth overview of the molecular interaction patterns between nNOS active site and inhibitors containing structurally diverse nitrogen heterocyclic compounds and highlight the structural properties needed to develop selective nNOS inhibitors. Previously published data allowed the usage of the structure-driven approach in the designing of selective nNOS inhibitors, which relies on the specific structural features required to achieve isoform-selectivity towards nNOS. The incorporation of chiral pyrrolidine ring, two aminopyridine heads, or a specific amino tail group, along with the inhibitor's capacity to adopt the curled conformation in the nNOS environment significantly strengthens the molecular interaction between the inhibitor and nNOS residues by forming specific electrostatic interactions and non-bonded contacts that are vital for isoform selectivity. Additional structure-activity relationship investigations are necessary to elucidate more structural characteristics that will ultimately resolve the exact structural basis required for isoform-selective inhibition of nNOS.

Antibacterial Activity and Antifungal Activity of Monomeric Alkaloids

Scientists are becoming alarmed by the rise in drug-resistant bacterial and fungal strains, which makes it more costly, time-consuming, and difficult to create new antimicrobials from unique chemical entities. Chemicals with pharmacological qualities, such as antibacterial and antifungal elements, can be found in plants. Alkaloids are a class of chemical compounds found in nature that mostly consist of basic nitrogen atoms. Biomedical science relies heavily on alkaloid compounds. Based on 241 papers published in peer-reviewed scientific publications within the last ten years (2014–2024), we examined 248 natural or synthesized monomeric alkaloids that have antifungal and antibacterial activity against Gram-positive and Gram-negative microorganisms. Based on their chemical structure, the chosen alkaloids were divided into four groups: polyamine alkaloids, alkaloids with nitrogen in the side chain, alkaloids with nitrogen heterocycles, and pseudoalkaloids. With MIC values of less than 1 µg/mL, compounds 91, 124, 125, 136–138, 163, 164, 191, 193, 195, 205 and 206 shown strong antibacterial activity. However, with MIC values of below 1 µg/mL, compounds 124, 125, 163, 164, 207, and 224 demonstrated strong antifungal activity. Given the rise in antibiotic resistance, these alkaloids are highly significant in regard to their potential to create novel antimicrobial drugs.

DECOMPOSITION MECHANISM OF ALKYLIDENE BRIDGED TETRAZOLES WITH DIFFERENT CARBON CHAIN LENGTHS.

Nitrogen-rich heterocycles, particularly tetrazole-based high-energy density materials (HEDMs) offer high performance, low sensitivity, and are eco-friendly. Despite the diversity of nitrogen-rich energetic heterocycles, many are sensitive to external stimuli, and the introduction of a methylene, ethylene, or C-C linkage between nitrogen-rich heterocycles is a successful strategy to improve mechanical sensitivity and thermal stability. Understanding the potential anomalous thermal or kinetic behavior of such molecules is crucial for the design of new HEDMs and practical applications of these molecules. We have investigated the influence of introducing an alkylidene bridge between the energetic nitrogen heterocycles on the decomposition mechanism and pathway of different bridged tetrazoles, namely 5,5'-Bis-1H-tetrazole, 1,2-Bis(5-tetrazolo)methane, and 1,2-Bis(5-tetrazolo)ethane, using thermal experiments, mass spectrometry, and computational analysis. Kinetic parameters were evaluated using a non-linear integral method, and decomposition pathways were proposed based on mass fragmentation data. Stability comparisons were made using HOMO-LUMO gap and electrostatic potential (ESP) values from computational calculations.

Degradation of Typical Nitrogen-Heterocyclic Compounds in Coal Gasification Wastewater via Catalytic Ozonation Processes

Degradation of Typical Nitrogen-Heterocyclic Compounds in Coal Gasification Wastewater via Catalytic Ozonation Processes

Selective oxidation of nitrogenous heterocyclic compounds by heat/peroxymonosulfate in phenol-rich wastewater

Selective oxidation of nitrogenous heterocyclic compounds by heat/peroxymonosulfate in phenol-rich wastewater

Synthesis, characterization and anticancer activity of zinc sulfide nanoparticle using heterocyclic Zn (II) thiosemicarbazone complex as a single source

The green synthesis of zinc sulphide nanoparticles (Zn S NPs) using Zn(II) complex as a single molecular precursor is gaining importance due to its simplicity, cost – effectiveness and pharmacologically active nature. Now – a- day’s nanobiotechnolgy is increasing at a fast rate due to its many possible applications in the biomedical and, pharmaceuticals fields. In this paper, we have reported the synthesis of Chalcogenide nanostructured pharmacologically active Zn S nanoparticles using Zn (II) Heterocyclic thiosemicarbazone Complex as a Single Source. Zn (II) complex was synthesized by the reaction between Schiff base ligand and Zinc acetate salt in 2:1 molar ratio. Thiosemicarbazone have a wide clinical antitumor spectrum with efficacy in various tumor types such as leukemia, pancreatic cancer, breast cancer, non- small cell lung cancer, cervical cancer, prostate cancer and bladder cancer. These compounds possessed significant antineoplastic activity when the carbonyl group attachment of the side chain was located at a position alpha to the heterocyclic nitrogen atom, whereas attachment of the side chain ꞵ or gamma to the heterocyclic nitrogen atom, resulted in inactive antitumor agents. In addition, replacement of the heterocyclic ring N with carbon also resulted in a biologically inactive compound suggesting that a conjugated N, N, S -tridentate donor set is essential for the biological activities of thiosemicarbazone ligands. In our study, for synthesis of Zn S nanoparticles, the synthesized Zn(II) complex of thiosemicarbazone ligand was treated with aqueous extract of Parmotrema perlatum flowers. The use of aqueous extract of Parmotrema perlatum flowers in the synthesis of ZnS particles plays a very important role in reducing reaction time, reducing minimum possibility of side reactions and conversion of metal complexes into its nanoparticles in a very less time. All synthesized compounds were characterized by various structural, morphological, electronic and vibrational spectroscopic techniques and also evaluate the pharmacological activities of compounds like antioxidant, anti-inflammatory and anticancer activities. The peaks at 3414.82 cm-1 in FT-IR spectra confirms the presence of –OH groups and other bioactive agents in the aqueous extract of Parmotrema perlatum flowers, which acts as a capping and stabilizing agents in the synthesis of Zn S nano particles. The effective results of anti-cancer activity of compounds showed that the ZnS nanoparticles shows good cytotoxic activity against human breast cancer cell lines (MCF-7) using MTT assay. In this study, normal human cell lines used as standard for comparison purpose. The CTC50 values of ZnS nanoparticles was found to be 49.375µg/ml respectively. Therefore, it could be concluded that this biogenic method is effective for synthesis of Zn S nanoparticles from Zn(II) complex with desirable properties for potential biomedical applications which can be consider as a good drug candidate for anti-cancer therapy

Design, Synthesis and Biological Activity Evaluation of β-Carboline Derivatives Containing Nitrogen Heterocycles.

A series of β-carboline derivatives containing nitrogen heterocycles were designed and synthesized. All compounds were screened for their antitumor activity against four human tumor cell lines (A549, K562, PC-3, T47D). Notably, compound N-(4-(morpholinomethyl)phenyl)-2-((5-(1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)-1,3,4-oxadiazol-2-yl)thio)acetamide (8q) exhibited significant inhibitory activity against PC-3 cells with an IC50 value of 9.86 µM. Importantly, compound 8q effectively suppressed both the proliferation and migration of PC-3 cells. Mechanistic studies revealed that compound 8q induced cell apoptosis and caused the accumulation of reactive oxygen species (ROS), leading to cell cycle arrest in the G0/G1 phase in PC-3 cells.

Sodium Copper Chlorophyllin: A Sustainable Bioinspired Catalyst for the Aerobic Oxidative Synthesis of Nitrogen Heterocycles and the Oxidative Cyanation of Tertiary Amines

AbstractA remarkably simple and straightforward protocol has been reported showcasing sodium copper chlorophyllin (SCC) as an eco‐friendly, bioinspired catalyst for the aerobic oxidative synthesis of pharmaceutically prevalent nitrogen‐containing heterocycles, such as benzimidazoles and quinoxalines. This reaction was performed in green solvent water, using the green oxidant, molecular oxygen. SCC displayed exceptional efficiency, congruent with the prevailing metal/non‐metal‐based catalyst regime without requiring additives. The SCC catalyst exhibited excellent recyclability upto three cycles for the benzimidazole synthesis reaction. This benign strategy was successfully applied in synthesizing a bioactive quinoxaline i. e., Tyrphostin AG1296, a promising candidate for melanoma treatment. The catalytic activity of SCC was explored for the synthesis of another privileged moiety i. e., α‐aminonitriles, via the α‐cyanation of tertiary amines under oxidative conditions. This reaction progressed with a mild, easy‐to‐use, convenient cyanide source, such as ethyl cyanoformate, and a green and attractive solvent, such as methanol, precluding acidic media. SCC catalyst was efficiently recycled upto three cycles for the α‐aminonitriles synthesis. Overall, the utility of a biodegradable, robust catalyst such as SCC, eco‐friendly solvents such as water and methanol, green oxidants such as O2, and mild reaction conditions, devoid of acidic additives, renders the present work viable for academic and industrial research.

Crystal structures and photophysical properties of mono- and dinuclear ZnII complexes flanked by triethylammonium

Two new zinc(II) complexes, triethylammonium dichlorido[2-(4-nitrophenyl)-4-phenylquinolin-8-olato]zinc(II), (C6H16N){Zn(C21H13N2O3)Cl2] (ZnOQ), and bis(triethylammonium) {2,2′-[1,4-phenylenebis(nitrilomethylidyne)]diphenolato}bis[dichloridozinc(II)], (C6H16N)2[Zn2(C20H14N2O2)Cl4] (ZnBS), were synthesized and their structures were determined using ESI–MS spectrometry, 1H NMR spectroscopy, and single-crystal X-ray diffraction. The results showed that the ligands 2-(4-nitrophenyl)-4-phenylquinolin-8-ol (HOQ) and N,N′-bis(2-hydroxybenzylidene)benzene-1,4-diamine (H2BS) were deprotonated by triethyl-amine, forming the counter-ion Et3NH+, which interacts via an N—H...O hydrogen bond with the ligand. The ZnII atoms have a distorted trigonal–pyramidal (ZnOQ) and distorted tetrahedral (ZnBS) geometries with a coordination number of four, coordinating with the ligands via N and O atoms. The N atoms coordinating with ZnII correspond to the heterocyclic nitrogen for the HOQ ligand, while for the H2BS ligand, it is the nitrogen of the imine (CH=N). The crystal packing of ZnOQ is characterized by C—H...π interactions, while that of ZnBS by C—H...Cl interactions. The emission spectra showed that ZnBS complex exhibits green fluorescence in the solid state with a small band-gap energy, and the ZnOQ complex does exhibit non-fluorescence.

Phosphorescent cyclometalated Ir(III) complexes with fluoranthene unit and their near-infrared (NIR) OLEDs showing NIR% higher than 99 %

With the aim to design and synthesize cyclometalated Ir(III) complexes with near-infrared (NIR) emission, a series of ppy-type ligands with fluoranthene unit have been synthesized bearing different aromatic nitrogen heterocycles of isoquinoline, quinoline, pyridine and benzo [d]thiazole. With these organic ligands, four [Ir (ppy)2 (acac)] complexes are prepared named as IrFTIQ, IrFTQL, IrFTPY and IrFTBZ. In solution, IrFTIQ can emit NIR phosphorescence at 738 nm, while IrFTQL (ca. 692 nm), IrFTPY (ca. 670 nm) and IrFTBZ (ca. 690 nm) are typical deep-red emitters. It should be noted that all these fluoranthene-based cyclometalated Ir(III) complexes show good electrochemical stability indicated by their reversible redox procedures. When doped in the emission layer of OLEDs, IrFTIQ and IrFTBZ can furnish NIR electroluminescence (EL) at 748 nm and 700 nm, respectively, while the devices with IrFTPY as emitter can furnish deep-red EL. Critically, the optimized OLED doped with IrFTIQ can achieve maximum external quantum efficiency (EQE) as high as 5.01 % and a radiance up to 6284 mW Sr−1 m−2. Critically, the NIR OLEDs based on IrFTIQ can furnish EL with NIR component (NIR%) of a total spectrum > 99 %. All these encouraging results definitely demonstrate the effectiveness of our molecular design strategy for the new-type Ir(III) NIR phosphorescent complexes and the great potential of the fluoranthene group in developing high-performance Ir-based NIR phosphors for OLEDs.

Rational design and synthesis of new pyrrolone candidates as prospective insecticidal agents against Culex pipiens L. Larvae.

As a result of its high reactivity, furan-2(3H)-one derivative 2 can be selected as a versatile and suitable candidate for building of novel nitrogen heterocyclic compounds. Consequently, furan-2(3H)-one derivative 2 and some nitrogen nucleophiles were utilized as starting materials for the formation of new pyridazinone and pyrrolone derivatives bearing naphthalene moiety. The continuous buildup of insecticide resistance is the main obstacle facing pest control measures. Pyrrole-based insecticides are a favourable choice due to their unique mode of action and no cross-resistance with traditional neurotoxic insecticides. The larvicidal activities of pyrrolone derivatives were assessed against field and laboratory strains of Culex pipiens larvae in comparison with chlorfenapyr (pyrrole insecticide). Compounds 17 (21.05µg/mL) > 9 (22.81µg/mL) > 15 (24.39µg/mL) > 10 (26.76µg/mL) > 16 (32.09µg/mL) were most effective against lab strain of C. pipiens larvae relative to chlorfenapyr (25.43µg/mL). While in field strain, 17 and 15 were the most toxic compounds followed by 9 > 10 > 16 > 2 with LC50 of 9.87, 10.76, 11.52, 12.68, 15.32 and 18.37µg/mL, respectively, compared with chlorfenapyr with 14.03µg/mL. The cytochrome P-450 monooxygenase activities were significantly increased in treated larvae of lab and field strains relative to untreated. The great variations in toxicity of the synthesized compounds were interpreted by structure-activity relationship study. The pyrrolone derivatives are effective against field and insecticide-resistant strains. Therefore, they are considered promising compounds to be integrated into pest management programs.

Highly Chemoselective Synthesis of α, α-Dideuterio Amines by the Reductive Deuteration of Thioamides Using Mild SmI2-D2O.

An efficient and chemoselective protocol for the single-electron-transfer (SET) reductive deuteration of thioamides using SmI2 and D2O is reported. This method uniquely produces α,α-dideuterio amines via a thio-ketyl radical intermediate without generating alcohol byproducts, distinguishing it from the SET reduction of amides. The inherent high reactivity of thioamides obviates the need for ligands like Et3N to improve the reducing power of SmI2, thereby enabling milder reaction conditions that are compatible with a broad range of sensitive functional groups. This protocol tolerates both primary and secondary aliphatic and aromatic thioamides, leading to the synthesis of 27 α,α-dideuterio amines and valuable deuterated nitrogen heterocycles with >95% deuterium incorporations.

A Review on Recent Synthesis and Diverse Biological Activities of Isoquinolone

Abstract: Isoquinolone scaffolds are among the most important core structures of nitrogen heterocyclic compounds, which possess vital roles in biological and physiological activities such as anti-tumor, anti-microbial, anti-leukemic, anti-malaria, anti-dengue, anti-HIV and anti-bacterial. Over the years, multiple studies have been done to synthesize these isoquinolone derivatives, and several authors have reported on various methods and synthetic routes to produce the target skeletons of isoquinolones. Therefore, many scientific communities have developed these compounds as the intended structure and evaluated their biological activities. Thus, this review confers several information on isoquinolone analogue synthetic strategies and their biological effects on mosquito- borne diseases.

Emergence of a distinct mechanism of C-N bond formation in photoenzymes.

C-N bond formation is integral to modern chemical synthesis due to the ubiquity of nitrogen heterocycles in small-molecule pharmaceuticals and agrochemicals. Alkene hydroamination with unactivated alkenes is an atom economical strategy for constructing these bonds. However, these reactions are challenging to render asymmetric when preparing fully substituted carbon stereocenters. Here, we report a photoenzymatic alkene hydroamination to prepare 2,2-disubstituted pyrrolidines by a Baeyer-Villiger Monooxygenase. Five rounds of protein engineering afforded a mutant, providing excellent product yield and stereoselectivity. Unlike related photochemical hydroaminations, which rely on the oxidation of the amine or alkene for C-N bond formation, this work exploits a through-space interaction of a reductively generated benzylic radical and the nitrogen lone pair. This antibonding interaction lowers the oxidation potential of the radical, enabling electron transfer to the flavin cofactor. Experiments indicate that the enzyme microenvironment is essential in enabling a novel C-N bond formation mechanism with no parallel in small molecule catalysis. Molecular dynamics simulations were performed to investigate the substrate in the enzyme active site which further support this hypothesis. This work is a rare example of an emerging mechanism in non-natural biocatalysis, where an enzyme has access to a mechanism that its individual components do not. Our study showcases the potential of enhancing emergent mechanisms using protein engineering to provide unique mechanistic solutions to unanswered challenges in chemical synthesis.

Supramolecular cyclodextrin complexes of biologically active nitrogen heterocycles

The review is devoted to the rapidly developing field of modern supramolecular chemistry - cyclodextrin complexes of biologically active nitrogen heterocycles, such as piperidines, piperazines, morpholines and pyridines. Interest in cyclodextrin complexes is growing due to the search and construction of supramolecular assemblies for targeted drug delivery. The latter is achieved as a result of supramolecular self-assembly, based on the principles of molecular recognition, and is one of the areas of modern chemistry, leading to the creation of new materials with new properties. This review fully demonstrates the ongoing scientific and practical interest in the problem of encapsulation with cyclodextrins, including nanoencapsulation. Encapsulation with cyclodextrins provides a wide range of advantages: obtaining solid dosage forms from liquid ones, stabilizing and protecting active substances from the adverse effects of external factors, increasing solubility, increasing bioavailability, reducing toxicity, prolonging action, etc. The presented review includes recent advances in the field of supramolecular complexes of biologically active nitrogen heterocycles with cyclodextrins and concludes with a discussion and identification of future promising directions for research. The review presents the results of supramolecular self-assembly of biologically active azaheterocycles with cyclodextrins.

Three-Component Synthesis of 1-Substituted 5-Aminotetrazoles Promoted by Bismuth Nitrate.

A nontoxic bismuth-promoted multicomponent synthesis of 5-aminotetrazoles and bistetrazoles is reported. The reaction of phenyl isothiocyanate, NaN3, and amine (primary aliphatic, aromatic, and aliphatic diamine) promoted by Bi(NO3)3·5H2O under microwave heating affords good yields, short reaction times, simple workup, and purification without column chromatography. A set of diagnostic 1H NMR signals was identified as a guide for quickly elucidating the exclusive (or main) regioisomer formed, with the stronger electron donor group located at heterocyclic nitrogen 1. This regioselectivity is strongly dependent on the electronic density of the amine. It is opposite to that obtained by several thiourea desulfurization methods promoted by thiophilic metals and metal-free protocols.

Novel Cyanide-Containing Porphyrins: Unleashing In Vitro Photodynamic Therapy Potential

Porphyrins, a class of four-pyrrole nitrogen heterocyclic compounds, have been used in photodynamic cancer therapy. In this study, three distinct pyridine cationic porphyrin photosensitizers were synthesized, each possessing unique side chains containing cyanide groups (H2-P1∼H2-P3). These photosensitizers were prepared using innovative synthetic methods. Subsequently, their theoretical photophysical properties were investigated using density functional theory (DFT). Notably, this research revealed that H2-P2 exhibits the smallest band gap (2.3548 eV) and the lowest energy gap (ΔEST =0.67 eV). Simultaneously, it was confirmed that these three photosensitizers could indeed produce singlet oxygen under illumination using DPBF as a singlet oxygen probe. Additionally, TPP was uesed as a reference to calculate the singlet oxygen yield for all three compounds, with H2-P2 demonstrating the highest yield (ΦΔ = 0.74). The experimental results aligned with the theoretical predictions. The phototoxicity and dark toxicity of the three photosensitizers were further evaluated using the MTT test. Remarkably, H2-P2 exhibited the highest phototoxicity toward HepG2 cancer cells (IC50<9.1 nM), while the lowest dark toxicity toward HUVEC cells (IC50>10 μM). These findings were supported by additional experiments involving cell staining and measurement of reactive oxygen species.

Flavor properties of post-heated fermented milk revealed by a comprehensive analysis based on volatile and non-volatile metabolites and sensory evaluation

Existing research on the post-heating processing of fermented milk has primarily focused on single post-heating treatments and the texture, while research on how changes in metabolites during different post-heating treatments affect flavor and sensory properties is limited. This study investigates the changes in volatile metabolites in fermented milk treated at different post-heating temperatures to determine the characteristic aroma types and analyzes the changes in non-volatile metabolites associated with aroma-active compounds or their precursors to clarify the causes of the altered flavor and sensory properties. The results showed that in the 65°C and 75°C treatments, 63 volatile compounds were produced by Strecker degradation, lipid oxidation and esterification to produce ketones and aldehydes. Significantly higher odor activity values for 2,3-butanedione, hexanoic acid, and esters and significantly lower odor activity values for 2-heptanone enhanced the frankincense odors and creaminess of the post-heated fermented milk. With temperatures increasing to 95°C, the increased ketones were primarily 2-heptanone, 2-nonanone, and 2-undecanone that originated from the oxidative decomposition of unsaturated phospholipids at high temperatures. The Maillard reaction of dipeptides produces nitrogenous heterocycles that trigger a caramelized flavor, while organic acids interact with proteins to form complexes that produce astringent flavors. These increase the oxidative off-flavors and reduce the overall palatability. These findings provide a scientific basis for optimizing the post-heating temperature process of fermented milk.

Synthesis and insecticidal assessment of nitrogenous heterocycles derived from 2-pyridone derivative against Culex pipiens L. Larvae

This study reports the synthesis of a novel 1,6-diamino-4-(2,4-dichlorophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (1) and its subsequent functionalization to yield a library of diverse heterocycles (2-10). The nucleophilicity of compound 1 was exploited to react with various electrophiles to afford a range of structurally enriched derivatives. The structures of all synthesized heterocycles were confirmed by elemental analysis and spectroscopic techniques as (FT-IR, 1H-NMR, 13C-NMR, and mass spectroscopy). Bioassays revealed significant larvicidal activity against mosquito larvae (Culex pipiens L.) for compounds 1-4, 6, 7 and 9. In silico docking studies suggest a potential mode of action through acetylcholinesterase (AChE) inhibition, potentially explaining the observed larvicidal effect. Additionally, interactions with other neuroreceptors were predicted. Finally, analyzing of the structure activity relationship (SAR) of the novel constructed heterocycles gives us a lot of interesting promising results for developing novel and sustainable mosquito control strategies.